Quinargine is a valuable intermediate for the manufacture of pharmacologically active compounds. Thus, as set for in European Patent Application No. 611,774, quinargine can be converted into pharmacologically active compounds which are primarily suitable for the treatment of viral infection, especially of such infections which are caused by HIV or other retroviruses.
Various reaction routes have been described for the manufacture of quinaldic acid derivatives. For example, Davis describes the reaction, which normally proceeds in good yields, of quinaldic acid chloride with primary and secondary amines, amino acids and amino acid esters under Schotten-Baumann conditions (J. Am. Chem. Soc. (1959), 24, 1691-1694). In the Schotten-Baumann reaction the substance to be acylated in 10% sodium hydroxide solution is shaken with an acid chloride until this has been consumed. The reaction is carried out using a large excess of alkali and acid chloride. However, in the manufacture of quinargine and its derivatives this procedure leads; only to moderate yields.
Anderson et al. describe the use of N-hydroxysuccinimide esters in peptide syntheses (Anclerson et al. (1964) J. Am. Chem. Soc. 86 , 1839-1842). Having regard to the greater water solubility, these esters are generally better suited, for the synthesis than the corresponding N-hydroxyphthalimide esters. The preparation of N-acyl-amino acid N-hydroxysuccinimide esters is generally effected by reacting an N-acyl-amino acid with N-hydroxysuccinimide according to the mixed anhydride method, particularly using dicyclohexylcarbodiimide (P. Stelzel in Houben-Weyl: "Methoden der organischen Chemie; Synthese von Peptiden", volume 15, part 2, p. 214, (1974)). The N-hydroxy-succinimide esters are then reacted with the corresponding amino acids in an organic-aqueous solvent mixture.
Wendlberger also describes the use of hydroxysuccinimide esters in the synthesis of peptides (Houben-Weyl: "Methoden der organischen Chemie; Synthese von Peptiden", volume 15, part 2 p. 130 (1974)). The high aminolysability of the N-hydroxy-succinimide esters compared with the low sensitivity to hydrolysis and alcoholysis enables peptide syntheses to be carried out not only in organic solvents, but also in organic-aqueous solvent mixtures such as ethanol/water, dioxan/water etc. Peptide syntheses with N-hydroxysuccinimide esters can also be carried out in a two-phase system such as dichloro-methane/water, etc.
The manufacture of 2S-N-(quinolin-2-ylcarbonyl)amino-3-oxo-3-aminopropanoic acid is described in International Patent Application WO95/20962. Here, the reaction of the corresponding pentafluorophenyl ester with asparagine is effected in a dioxanwater mixture.
All of the aforementioned processes have considerable disadvantages when they are used for the manufacture of quinargine. Thus, the reaction proceeds with yields which are far from quantitative. This is primarily due to the formation of a byproduct by hydrolysis. Consequently, the reaction mixture has to be subjected to an expensive working-up. Moreover, problematic byproducts such as the toxic pentafluorophenol (WO95/20962) result during the manufacture of quinargine and, respectively, quinargine derivatives, so that the large-scale manufacture using methods of the state of the art can not be achieved satisfactorily.